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To reduce average surgical-site infection (SSI) rates to less than 7.5%, as well as other complications by incrementally implementing an SSI prevention care bundle in maternity: (1) ChloraPrep; (2) PICO dressings, performing elective cesarean sections in a main theater rather than a labor ward and warming blankets; (3) vaginal cleansing; and (4) Hibiscrub.In this prospective cohort study, the association between categorical variables was assessed by χIn all, 1682 women (mean age 33.1 ± 5.2 years) underwent either elective (53.9%) or emergency (46.1%) cesarean section. After a small initial increase (10.0%-11.8%), SSI progressively declined to 4.4% (χThe maternal SSI prevention care bundle is simple and inexpensive; it effectively reduces SSI after a cesarean section and should be offered routinely to women undergoing cesarean section.

Parasympathetic nerve-mediated contractions of detrusor smooth muscle are generated by ATP and acetylcholine (ACh) release from efferent nerve terminals. In humans, ACh is responsible for detrusor contractions in normal human bladders, whereas ATP has an additional role in overactive bladder pathologies. The ATP metabolite, adenosine, relaxes nerve-mediated contractions, with a potential action via presynaptic adenosine A1 receptor activation and subsequent suppression of neuronal ATP release. We investigated the effect of A1 receptor activation and downstream cAMP-dependent pathways on nerve-mediated ATP and ACh release, and detrusor contraction in mouse detrusor. Bladders from male C57BL/6 mice (12 wk) were used for in vitro experiments. Upon electrical field stimulation of intact preparations (detrusor and mucosal layers), ATP or ACh release was measured simultaneously with tension recordings. Activation of A1 receptors by adenosine or exogenous agonists reduced the lower frequency component of nerve-mediated contractions and neuronal ATP release. The A1 receptor antagonist abolished these effects. A1 receptor activation inhibits adenylyl cyclase (AC) activity and cAMP generation. The effect of A1 receptor activation was mimicked by a PKA antagonist but not by modulators of exchange proteins activated by cAMP, demonstrating that modulation of nerve-mediated ATP release is via PKA. Adenosine had no effect on ACh release or the higher frequency component of nerve-mediated contractions. Differential regulation of neurotransmitter release is possible at the detrusor nerve-muscle junction, as demonstrated by A1 receptor activation, and downstream inhibition of AC, cAMP generation, and PKA. The ability to specifically attenuate ATP release offers a potential to target purinergic motor pathways enhanced in overactive bladder pathologies.

Objective The use of herbal medicinal supplements has gained huge popularity world-wide, but scientific evidence of their effectiveness and safety remains scarce. Ashwagandha (Withania somnifera) is one such product, claimed to alleviate pain and anxiety by lowering circulating cortisol levels. Withanolides, which are the principal bioactive compounds of ashwagandha, are naturally occurring steroids and may suppress adrenal function. Here, we describe the effect of ashwagandha on adrenal function of a 41-year-old woman with a low body mass index and who suffered chronic pain and lethargy. Methods Adrenal function was assessed by the short Synacthen test (SST) during and after treatment with ashwagandha supplementation. Results Whilst taking daily ashwagandha supplement (21.4 mg of Withanolides), for ten weeks, a SST showed a minimal response to 250 μg of an intramuscular injection of Synacthen (tetracosactide): cortisol levels at T0min = 287 nmol/l, T30min = 289 nmol/l, and T60min = 328 nmol/l; from a morning baseline cortisol level of 480 nmol/l prior to taking the supplement. Ashwagandha was discontinued for two weeks, and a repeat SST was performed showing a completely normal adrenal response: cortisol level at T0min = 275 nmol/l, T30min = 623 nmol/l and T60min = 674 nmol/l. Conclusion Ten weeks of ashwagandha supplementation was associated with adrenal hypofunction, which was reversible after a two-week break. Individuals taking ashwagandha should be aware of this potentially detrimental effect. Future studies are suggested to assess whether long-term treatment with ashwagandha could lead to permanent suppression of adrenal function, and to elucidate the effects of ashwagandha compounds on adrenal steroidogenic pathway and hypothalamic–pituitary–adrenal axis.

Hip fracture in older adults is associated with poor prognosis. We tested the hypothesis that a single standardized measure, pre-fracture mobility, can be used as an early indicator of patients at high health risk after a hip fracture. Analysis of prospectively collected data of older adults admitted with a hip fracture between April-2009 and June-2019 in a single NHS hospital, UK. Pre-fracture mobility status (freely mobile, mobilising outdoors with one aid or with two aids, and limited to indoors), was used to predict length of stay (LOS) and mortality in hospital, and discharge destination. Among 3073 (2231 women, 842 men) admitted from their own home (mean ± SD age = 82.7 ± 9.3 yr), 159 died and 2914 survived to discharge: 1834 back to their home, 772 to rehabilitation, 66 to residential care, 141 to nursing care and 101 to unknown destinations. Compared with LOS of 15.9 ± 15.6 days in patients who mobilised freely before fracture (reference), those who were able to mobilise outdoors with one aid stayed 3.5 days, and those with two aids or confined to indoor mobility stayed one week longer in hospital. In-patient mortality was increased among patients who mobilised outdoors with two aids: OR = 2.1 (95%CI = 1.3–3.3), and those limited to indoors: OR = 2.1 (1.3–1.5). Finally, a change in residence on discharge was more likely in those who mobilised outdoors with two aids (OR = 1.8, 95%CI = 1.2–2.6), and those limited to indoors (OR = 1.9, 95%CI = 1.2–2.9). In conclusion, pre-fracture mobility may be a useful early indicator for identifying patients at increased risk of adverse outcomes after an acute hip fracture.

Background The present study assessed factors associated with the risk of surgical site infections (SSI) after a caesarean section (C-section). Methods Data were collected in 1682 women undergoing elective (53.9%) and emergency (46.1%) C-sections between 1st August 2020, and 30th December 2021, at a National Health Service hospital (Surrey, UK). Results At the time of C-section, the mean age was 33.1 yr (SD ± 5.2). Compared to women with BMI 2, those with a BMI ≥ 35 kg/m2 had a greater risk of SSI, OR 4.07 (95%CI 2.48–6.69). Women with a history of smoking had a greater risk of SSI than those who had never smoked, OR 1.69 (95%CI 1.05–2.27). Women with a BMI ≥ 30 kg/m2 and had a smoking history or emergency C-section had 3- to tenfold increases for these adverse outcomes. Ethnic minority, diabetes or previous C-section did not associate with any of the outcomes. Conclusions High BMI, smoking, and emergency C-section are independent risk factors for SSI from C-section. Women planning conception should avoid excess body weight and smoking. Women with diabetes and from ethnic minority backgrounds did not have increased risks of SSI, indicating a consistent standard of care for all patients.

In this study of patients admitted with COVID-19, we examined differences between the two waves in patient characteristics and outcomes. Data were collected from the first COVID-19 admission to the end of study (01/03/2020–31/03/2021). Data were adjusted for age and sex and presented as odds ratios (OR) with 95% confidence intervals (CI). Among 12,471 admissions, 1452 (11.6%) patients were diagnosed with COVID-19. On admission, the mean (± SD) age of patients with other causes was 68.3 years (± 19.8) and those with COVID-19 in wave 1 was 69.4 years (± 18.0) and wave 2 was 66.2 years (± 18.4). Corresponding ages at discharge were 67.5 years (± 19.7), 63.9 years (± 18.0) and 62.4 years (± 18.0). The highest proportion of total admissions was among the oldest group (≥ 80 years) in wave 1 (35.0%). When compared with patients admitted with other causes, those admitted with COVID-19 in wave 1 and in wave 2 were more frequent in the 40–59 year band: 20.8, 24.6 and 30.0%; consisted of more male patients: 47.5, 57.6 and 58.8%; and a high LACE (Length of stay, Acuity of admission, Comorbidity and Emergency department visits) index (score ≥ 10): 39.4, 61.3 and 50.3%. Compared to wave-2 patients, those admitted in wave 1 had greater risk of death in hospital: OR = 1.58 (1.18–2.12) and within 30 days of discharge: OR = 2.91 (1.40–6.04). Survivors of COVID-19 in wave 1 stayed longer in hospital (median = 6.5 days; interquartile range = 2.9–12.0) as compared to survivors from wave 2 (4.5 days; interquartile range = 1.9–8.7). Patient characteristics differed significantly between the two waves of COVID-19 pandemic. There was an improvement in outcomes in wave 2, including shorter length of stay in hospital and reduction of mortality.

PURPOSE: The urinary bladder generates phasic contractions via action potentials generated in pre- and then postganglionic neurons. Whilst the frequency-dependence of postganglionic neurons to generate contractions has been quantified, the dynamic range of preganglionic neurons is less clear and if intramural ganglia exert frequency-dependent modulation of transmission between pre- and postganglionic neurons. The phosphodiesterase type 5 inhibitor sildenafil reduces neurotransmitter release from postganglionic fibres to detrusor smooth muscle and an additional question was if there was also a preganglionic action. This study aimed to compare the frequency range of bladder contractile activation by pre- and postganglionic stimulation in pig and rat bladders and if sildenafil exerted additional preganglionic actions.METHODS: An arterially-perfused ex vivo pig bladder preparation was used for preganglionic (pelvic nerve) and mixed pre-and postganglionic (direct bladder wall) stimulation at 36°C and postganglionic mediated contractions achieved by field-stimulation of in vitro isolated detrusor strips. With rats, pelvic nerve stimulation was carried out in vivo and postganglionic stimulation also with isolated detrusor strips.RESULTS: All contractions were abolished by 2% lignocaine indicating they are nerve-mediated. Stimulation targets were verified with hexamethonium that completely abolished pelvic nerve responses by had no effect on detrusor strips; responses to mixed bladder wall stimulation were partially reduced. The frequency-dependence of contractile activation was similar whether by pre- or postganglionic stimulation in both pigs and rats. Sildenafil reduced contractions to preganglionic stimulation significantly more than to postganglionic stimulation. Mixed pre- and postganglionic stimulation were reduced by an intermediate extent.CONCLUSION: Intramural ganglia offer no frequency-dependent modulation under the experimental conditions used here and the sildenafil data are consistent with multiple sites of action underlying generation of bladder contractions. A translational aspect of these findings is discussed in terms of setting stimulation parameters for neuromodulation protocols.

The Blue Book published by the British Orthopaedic Association and British Geriatrics Society, together with the introduction of National Hip Fracture Database Audit and Best Practice Tariff, have been influential in improving hip fracture care. We examined ten-year (2009–2019) changes in hip fracture outcomes after establishing an orthogeriatric service based on these initiatives, in 1081 men and 2891 women (mean age = 83.5 ± 9.1 years). Temporal trends in the annual percentage change (APC) of outcomes were identified using the Joinpoint Regression Program v4.7.0.0. The proportions of patients operated beyond 36 h of admission fell sharply during the first two years: APC = − 53.7% (95% CI − 68.3, − 5.2, P = 0.003), followed by a small rise thereafter: APC = 5.8% (95% CI 0.5, 11.3, P = 0.036). Hip surgery increased progressively in patients > 90 years old: APC = 3.3 (95% CI 1.0, 5.8, P = 0.011) and those with American Society of Anaesthesiologists grade ≥ 3: APC = 12.4 (95% CI 8.8, 16.1, P P = 0.050) and also a significant decline in mortality amongst those > 90 years old: APC = − 7.1 (95% CI − 12.6, − 1.3, P = 0.024). Prolonged length of stay (> 23 days) declined from 2013: APC = − 24.6% (95% CI − 31.2, − 17.4, P P = 0.017) and sharply thereafter (APC = − 47.5%, 95%CI − 71.7, − 2.7, P = 0.043). The rate of patients returning home was decreasing (APC = − 2.9, 95% CI − 5.1, − 0.7, P = 0.016), whilst new discharge to rehabilitation was increasing (APC = 8.4, 95% CI 4.0, 13.0; P = 0.002). In conclusion, the establishment of an orthogeriatric service was associated with a reduction of elapsed time to hip surgery, a progressive increase in surgery carried out on high-risk adults and a decline in adverse outcomes.

Background Obesity, obstructive sleep apnoea (OSA) and hypertension frequently coexist and are associated with elevated cortisol levels. Identification and treatment of such patients is important when investigating for suspected Cushing's syndrome and hypertension. Studies of the impact of continuous positive airway pressure (CPAP) on cortisol and blood pressure are limited by small sample size and show conflicting findings. We conducted a meta-analysis to document changes in the levels of cortisol and blood pressure in response to CPAP treatment of OSA. Methods Meta-analysis was conducted using RevMan (v5.3) and expressed in standardised mean difference (SMD) for catecholamines and mean difference (MD) for systolic (SBP) and diastolic blood pressure (DBP). The quality of the studies was evaluated using standard tools for assessing the risk of bias. Results A total of 22 studies met our search criteria; they consisted of 16 prospective cohort studies (PCS) that recruited 385 participants and six randomized control trials (RCT) totalling 252 participants. Range of mean age was 41-62yr and BMI 27.2-35.1kg/m2 . CPAP treatment reduced plasma cortisol levels in PCS: SMD = -0.28 (95%CI = -0.45 to -0.12), I 2 = 0%, p = 0.79 and in RCT: SMD = -0.39 (95%CI = -0.75 to -0.03), I 2 = 28.3%, p = 0.25. CPAP treatment reduced SBP by 5.4 mmHg (95% confidence interval =1.7-9.1) and DBP by 3.3 mmHg (95% confidence interval = 1.0-5.7). Inter-study heterogeneity was low for all studies. Bias in most RCT arose from the lack of blinding of participants and personnel. Conclusion CPAP treatment in individuals with OSA reduces cortisol levels and blood pressure. This article is protected by copyright. All rights reserved.

Complications following thrombolysis for stroke are well documented, and mostly concentrated on haemorrhage. However, the consequences of patients who experience any immediate thrombolysis-related complications (TRC) compared to patients without immediate TRC have not been examined. Prospectively collected data from the Sentinel Stroke National Audit Programme were analysed. Thrombolysis was performed in 451 patients (52.1% men; 75.3 years ± 13.2) admitted with acute ischaemic stroke (AIS) in four UK centres between 2014 and 2016. Adverse consequences following immediate TRC were assessed using logistic regression, adjusted for age, sex and co-morbidities. Twenty-nine patients (6.4%) acquired immediate TRC. Compared to patients without, individuals with immediate TRC had greater adjusted risks of: moderately-severe or severe stroke (National Institutes of Health for Stroke Scale score ≥ 16) at 24-h (5.7% vs 24.7%, OR 3.9, 95% CI 1.4–11.1); worst level of consciousness (LOC) in the first 7 days (score ≥ 1; 25.0 vs 60.7, OR 4.6, 95% CI 2.1–10.2); urinary tract infection or pneumonia within 7-days of admission (13.5% vs 39.3%, OR 3.2, 95% CI 1.3–7.7); length of stay (LOS) on hyperacute stroke unit (HASU) ≥ 2 weeks (34.7% vs 66.7%, OR 5.2, 95% CI 1.5–18.4); mortality (13.0% vs 41.4%, OR 3.7, 95% CI 1.6–8.4); moderately-severe or severe disability (modified Rankin Scale score ≥ 4) at discharge (26.8% vs 65.5%, OR 4.7, 95% CI 2.1–10.9); palliative care by discharge date (5.1% vs 24.1%, OR 5.1, 95% CI 1.7–15.7). The median LOS on the HASU was longer (7 days vs 30 days, Kruskal–Wallis test: χ2 = 8.9, p = 0.003) while stroke severity did not improve (NIHSS score at 24-h post-thrombolysis minus NIHSS score at arrival = − 4 vs 0, χ2 = 24.3, p

Construction workers are at increased health risk due to exposure to respirable crystalline silica (RCS) dust. We examined differences in health risk among non-manual and manual employees in the construction industry. The participants were drawn randomly from the construction industry by targeting UK construction workers’ websites. Online survey of construction industry employees using a questionnaire consisted of 17 items to obtain information on demographic data, employment history and health risk exposure. Chi-squared tests were used to explore differences in health risk between manual and non-manual employees, and logistic regression to determine the risk of adverse events in manual workers. Of the 47 employees invited, 45 completed the questionnaire (95% response rate). Seventeen were non-manual (professional, project managers and managers) and 28 were manual employees (tradesmen and construction workers). There was a significantly higher percentage of non-manual employees below 45 years than older group (70.6% vs 39.3%; χ2 = 4.2, p = 0.039) and they worked less than 20 years than those working longer (82.4% vs 32.1%; χ2 = 10.7, p = 0.001). Compared to non-manual workers, manual workers were more likely to work >20 years: OR = 2.2 (95% CI = 1.3–3.6); be exposed to RCS dust and smoke: unadjusted OR = 1.8 (1.1–3.1), age and length of time working in construction industry adjusted OR = 2.2(1.2–4.2); and have breathing problems: unadjusted OR = 3.9 (1.5–10.4), age, smoking and length of time working in construction industry adjusted OR = 3.7 (1.1–12.5). The risk of breathing problems was increased among individuals working more than 20 years: OR = 4.8 (1.2–18.6), exposed to dust and smoking: unadjusted OR = 3.8 (1.0–14.1), age and length of time working in construction industry adjusted OR = 5.4 (1.2–24.4), whilst those with adequate information on health hazards were associated with lower risk of breathing problems. There is an increased risk of exposure to RCS dust and pulmonary symptoms among manual employees in the construction industry. Further efforts are required to provide greater protection for this group of workers to reduce their health risk.

Frequent emergency readmissions may associate with health consequences. We examined the association between readmissions within 28 days of hospital discharge and mortality in 32,270 alive-discharge episodes (18–107 years). Data collected between 1 April 2017 and 31 March 2019 are presented as age- and sex-adjusted hazard ratios (HR) with 95% confidence interval (CI). Compared with no readmission, mortality risk over a 2-year period was increased with one non-identical admission–readmission (AR) episode: HR = 2.4 (2.2–2.7), two or more non-identical AR episodes: HR = 3.0 (2.7–3.4), one identical AR episode: HR = 4.7 (3.6–6.1) and two or more identical AR episodes: HR = 5.0 (3.8–6.7). Eight conditions associated with AR episodes had increased risk of mortality including congestive heart failure: HR = 2.7 (2.2–3.2), chronic pulmonary obstructive disease: HR = 3.0 (2.5–3.6), pneumonia: HR = 2.0 (1.8–2.3), sepsis: HR = 2.2 (1.9–2.5), endocrine disorders: HR = 1.9 (1.6–2.3), urinary tract infection: HR = 1.5 (1.3–1.7), psychiatric disorders: HR = 1.5 (1.1–2.1) and haematological disorders: HR = 1.5 (1.2–1.9). Frequent identical AR episodes, particularly from chronic and age-related conditions, are associated with increased mortality.

AimsTo determine whether the amount of ATP, prostaglandin E2 (PGE2), and acetylcholine (ACh) in voided urine are influenced enough by that released within the lower urinary tract (LUT) for them to be useful biomarkers of bladder function.MethodsParticipants without LUT symptoms collected total urine voids at 15, 30, 60, and 120 min (20 males/23 females) and 240 min (18 males/26 females) following the previous void. Aliquots of urine were immediately frozen at −20°C and later used to measure ATP (luciferin‐luciferase), PGE2 (enzyme‐linked immunosorbent assay), ACh (mass spectrometry), creatinine (colorimetric), and lactose dehydrogenase (colorimetric).ResultsThe amount of ATP in voided urine correlated strongly with the rate of urine production, suggesting that the majority, if not all, the ATP in voided urine has an LUT, and likely bladder, origin. In contrast, there appeared to be no significant net LUTs release of creatinine or ACh into the urine. PGE2 was intermediate with an LUT component that increased with urine production rate and contributed about 25% of the total at 1 ml/min in women but a smaller fraction in men.ConclusionWhereas the majority of the ATP measured within the voided urine originates in the LUT, ACh reflects that extracted from the plasma in the kidneys and PGE2 is a mixture of both sources. ATP has the most potential as a biomarker of benign bladder disorders. Expressing urinary ATP concentration relative to creatinine concentration is questioned in light of these results.

Summary Congenital lower urinary tract disorders are a family of diseases affecting both urinary storage and voiding as well as upstream kidney function. Current treatments include surgical reconstruction but many children still fail to achieve urethral continence or progress to chronic kidney disease. New therapies can only be achieved through undertaking research studies to enhance our understanding of congenital lower urinary tract disorders. Animal models form a critical component of this research, a corner of the triangle composed of human in-vitro studies and clinical research. We describe the current animal models for two rare congenital bladder disorders, posterior urethral valves (PUV) and bladder exstrophy (BE). We highlight important areas for researchers to consider when deciding which animal model to use to address particular research questions and outline the strengths and weaknesses of current models available for PUV and BE. Finally, we present ideas for refining animal models for PUV and BE in the future to stimulate future researchers and help them formulate their thinking when working in this field.

We evaluated factors and outcomes associated with elapsed time to surgery (ETTS) in 1,081 men and 2,891 women (mean age 83.5 years ±9.1) undergoing hip fracture surgery (from 2009–2019). Mortality rates were 4.8%, 6.3%, 6.2% and 10.3% (chi-squared 19.0; p19 days were 31.9%, 32.8%, 33.8% and 43.2% (chi-squared 18.5; p19 days (OR 1.34; 95% CI 1.02–1.75). The median (interquartile range (IQR)) LOS for ETTS

Patients admitted with a cervical fracture are twice as likely to die within 30 days of injury than those with a hip fracture. However, guidelines for the management of cervical fractures are less available than for hip fractures. We hypothesise that outcomes may differ between these types of fractures. We analysed 1359 patients (406 men, 953 women) with mean age of 83.8 years (standard deviation = 8.7) admitted to a National Health Service hospital in 2013–2019 with a cervical (7.5%) or hip fracture (92.5%) of similar age. The association of cervical fracture (hip fracture as reference), hospital length of stay (LOS), co-morbidities, age and sex with outcomes (acute delirium, new pressure ulcer, and discharge to residential/nursing care) was assessed by stepwise multivariate logistic regression. Acute delirium without history of dementia was increased with cervical fractures: odds ratio (OR) = 2.4, 95% confidence interval (CI) = 1.3–4.7, age ≥ 80 years: OR = 3.5 (95% CI = 1.9–6.4), history of stroke: OR = 1.8 (95% CI = 1.0–3.1) and ischaemic heart disease: OR = 1.9 (95% CI = 1.1–3.6); pressure ulcers was increased with cervical fractures: OR = 10.9 (95% CI = 5.3–22.7), LOS of 2–3 weeks: OR = 3.0 (95% CI = 1.2–7.5) and LOS of ≥ 3 weeks: OR = 4.9, 95% CI = 2.2–11.0; and discharge to residential/nursing care was increased with cervical fractures: OR = 3.2 (95% CI = 1.4–7.0), LOS of ≥ 3 weeks: OR = 4.4 (95% CI = 2.5–7.6), dementia: OR = 2.7 (95% CI = 1.6–4.7), Parkinson’s disease: OR = 3.4 (95% CI = 1.3–8.8), and age ≥ 80 years: OR = 2.7 (95% CI = 1.3–5.6). In conclusion, compared with hip fracture, cervical fracture is more likely to associate with acute delirium and pressure ulcers, and for discharge to residency of high level of care, independent of established risk factors.

The Nottingham Hip Fracture Score (NHFS) has been developed for predicting 30-day and 1-year mortality after hip fracture. We hypothesise that NHFS may also predict other adverse events. Data from 666 patients (190 men, 476 women), aged 60.2–103.4 years, admitted with a hip fracture to a single centre from 1/10/2015 and 7/12/2017 were analysed. The ability of NHFS to predict mobility within 1 day after surgery, length of stay (LOS) find mortality, and discharge destination was evaluated by receiver operating characteristic curves and two-graph plots. The area under the curve (95% confidence interval [CI]) for predicting mortality was 67.4% (58.4–76.4%), prolonged LOS was 59.0% (54.0–64.0%), discharge to residential/nursing care was 62.3% (54.0–71.5%), and any two of failure to mobilise, prolonged LOS or discharge to residential/nursing care was 64.8% (59.0–70.6%). NHFS thresholds at 4 and 7 corresponding to the lower and upper limits of intermediate range where sensitivity and specificity equal 90% were identified for mortality and prolonged LOS, and 4 and 6 for discharge to residential/nursing care, which were used to create three risk categories. Compared with the low risk group (NHFS = 0–4), the high risk group (NHFS = 7–10 or 6–10) had increased risk of in-patient mortality: rates = 2.0% versus 7.1%, OR (95% CI) = 3.8 (1.5–9.9), failure to mobilise within 1 day of surgery: rates = 18.9% versus 28.3%, OR = 1.7 (1.0–2.8), prolonged LOS (> 17 days): rates = 20.3% versus 33.9%, OR = 2.2 (1.3–3.3), discharge to residential/nursing care: rates = 4.5% vs 12.3%, OR = 3.0 (1.4–6.4), and any two of failure to mobilise, prolonged LOS or discharge to residential/nursing care: rates = 10.5% versus 28.6%, 3.4 (95% CI 1.9–6.0), and stayed 4.1 days (1.5–6.7 days) longer in hospital. High NHFS associates with increased risk of mortality, prolonged LOS and discharge to residential/nursing care, lending further support for its use to identify adverse events.

Background The LACE index scoring tool (Length of stay, Acuity of admission, Co-morbidities and Emergency department visits) has been designed to predict hospital readmissions. We evaluated the ability of the LACE index to predict age-specific frequent admissions and mortality. Methods Analysis of prospectively collected data of alive-discharge episodes between 01/04/2017 and 31/03/2019 in an NHS hospital. Data on 14,878 men and 17,392 women of mean age 64.0 years, SD = 20.5, range 18.0–106.7 years were analysed. The association of the LACE index with frequency of all-cause readmissions within 28 days of discharge and over a 2-year period, and with all-cause mortality within 30 days or within 6 months after discharge from hospital were evaluated. Results Within LACE index scores of 0–4, 5–9 or ≥ 10, the proportions of readmission ≥ 2 times within 28 days of discharge were 0.1, 1.3 and 9.2% (χ2 = 3070, p 2 = 3364, p p p Conclusions The LACE index predicts short-term and long-term frequent admissions and short-term and medium-term mortality, most pronounced among younger individuals, after hospital discharge.

New Findings: What is the central question of this study? Is the frequency dependence of co-transmitter release from postganglionic nerve fibres different for each transmitter? What is the main finding and its importance? Release of co-transmitters from the parasympathetic supply to detrusor smooth muscle can be independently regulated. This offers a targeted drug model to reduce selectively the release of transmitter associated with human pathologies (ATP) and may also be applicable to other smooth muscle-based disorders of visceral tissues. Abstract: Nerve-mediated contractions of detrusor smooth muscle are mediated by acetylcholine (ACh) and ATP release in most animals. However, with the normal human bladder, only ACh is a functional transmitter, but in benign pathologies such as overactive bladder (OAB), ATP re-emerges as a secondary transmitter. The selective regulation of ATP release offers a therapeutic approach to manage OAB, in contrast to current primary strategies that target ACh actions. However, the release characteristics of nerve-mediated ACh and ATP are poorly defined and this study aimed to measure the frequency dependence of ACh and ATP release and determine if selective regulation of ATP or ACh was possible. Experiments were carried out in vitro with mouse detrusor with nerve-mediated ATP and ACh release measured simultaneously with tension recording. ATP was released in two frequency-dependent components, both at lower frequencies (mid-range 0.4 and 5.5Hz stimulation) compared to a single compartment release of ACh at 14Hz. Intervention with the phosphodiesterase type-5 inhibitor sildenafil attenuated ATP release, equally from both components, but had no effect on ACh release. These data demonstrate that nerve-mediated ACh and ATP release characteristics are distinct and may be separately manipulated. This offers a potential targeted drug model to manage benign lower urinary tract conditions such as OAB.

Objective Hospital-onset stroke (HOS) is associated with poorer outcomes than community-onset stroke (COS). Previous studies have variably documented patient characteristics and outcome measures; here, we compare in detail characteristics, management and outcomes of HOS and COS. Methods A total of 1656 men (mean age ± SD = 73.1 years ± 13.2) and 1653 women (79.3 years ± 13.0), with data prospectively collected (2014–2016) from the Sentinel Stroke National Audit Programme, were admitted with acute stroke in four UK hyperacute stroke units (HASU). Associations between variables were examined by chi-squared tests and multivariable logistic regression (COS as reference). Results There were 272 HOS and 3037 COS patients with mean ages of 80.2 years ± 12.5 and 76.4 years ± SD13.5 and equal sex distribution. Compared to COS, HOS had higher proportions ≥ 80 years (64.0% vs 46.4%), congestive heart failure (16.9% vs 4.9%), atrial fibrillation (25.0% vs 19.7%) and pre-stroke disability (9.6% vs 5.1%), and similar history of stroke, hypertension, diabetes, stroke type and severity of stroke. After age, sex and co-morbidities adjustments, HOS had greater risk of pneumonia: OR (95%CI) = 1.9 (1.3–2.6); malnutrition: OR = 2.2 (1.7–2.9); immediate thrombolysis complications: OR = 5.3 (1.5–18.2); length of stay on HASU > 3 weeks: OR = 2.5 (1.8–3.4); post-stroke disability: OR = 1.8 (1.4–2.4); and in-hospital mortality: OR = 1.8 (1.2–2.4), as well as greater support at discharge including palliative care: OR = 1.9 (1.3–2.8); nursing care: OR = 2.0 (1.3–4.0), help for daily living activities: OR = 1.6 (1.1–2.2); and joint-care planning: OR = 1.5 (1.1–1.9). Conclusions This detailed analysis of underlying differences in subject characteristics between patients with HOS or COS and adverse consequences provides further insights into understanding poorer outcomes associated with HOS.

Nocturia is a prevalent condition and may result from nocturnal polyuria, whereby overnight urine production is excessive. Anecdotal cases of idiopathic nocturnal polyuria in which cerebrospinal fluid (CSF) disorders were identified suggest a potential mechanism. The skull constrains three circulatory systems: the CSF, interstitial fluid, and vascular supply. For each, fluid dynamics (pressure, volume, and flow) are closely regulated and adapt to changes such as recumbency and circadian variation. Pathologies disrupting this regulation, and thus impairing intracranial fluid dynamics, will place the brain environment at risk. Hence, compensatory responses are needed to maintain safe limits and prevent neurological deficits. We hypothesise that a change in the fluid dynamics for the intracranial CSF, interstitial, or vascular circulation means that positional or circadian changes during sleep trigger compensatory hormonal responses to protect the brain, but these also cause nocturnal polyuria. Natriuretic hormones are candidate mediators for protection against excess intracranial pressure or volume.Patient summaryA need to pass urine during the night, which is called nocturia, may be because of excessive overnight urine production. We propose that changes in fluid dynamics in the brain caused by lying down or daily body rhythms may trigger the release of hormones that could be a factor in nighttime urine production. This hypothesis should be explored in further investigations.

Benign prostatic hyperplasia (BPH) is a feature of ageing males. Up to half demonstrate bladder outlet obstruction (BOO) with associated lower urinary tract symptoms (LUTS) including bladder overactivity. Current therapies to reduce obstruction, such as α1-adrenoceptor antagonists and 5α-reductase inhibitors, are not effective in all patients. The phosphodiesterase-5 inhibitor (PDE5I), tadalafil, is also approved to treat BPH and LUTS suggesting a role for nitric oxide (NO•), soluble guanylate cyclase (sGC), and cGMP signalling pathways. However, PDE5I refractoriness can develop for reasons including nitrergic nerve damage and decreased NO• production, or inflammation-related oxidation of the sGC haem group, normally maintained in a reduced state by the cofactor, cytochrome-b5-reductase 3 (CYB5R3). sGC activators, such as cinaciguat (BAY 58-2667), have been developed to enhance sGC activity in the absence of NO• or when sGC is oxidised. Accordingly, their effects on the prostate and LUT function of aged mice were evaluated. Aged mice (≥24 months) demonstrated a functional BPH/BOO phenotype, compared to adult animals (2-12 months), with low, delayed voiding responses and elevated intravesical pressures as measured by telemetric cystometry. This was consistent with outflow tract histological and molecular data that showed urethral constriction, increased prostate weight, greater collagen deposition and cellular hyperplasia. All changes in aged animals were attenuated by daily oral treatment with cinaciguat for two weeks, without effect on serum testosterone levels. Cinaciguat had only transient (1 h) cardiovascular effects with oral gavage suggesting a positive safety profile. The benefit of cinaciguat was suggested by its reversal of an overactive cystometric profile in CYB5R3 smooth muscle knock-out mice that mirrors a profile of oxidative dysfunction where PDE5I may not be effective. Thus, the aged male mouse is a suitable model for BPH-induced BOO and cinaciguat has a demonstrated ability to reduce prostate-induced obstruction and consequent effects on bladder function. This article is protected by copyright. All rights reserved.

Knowledge of the participation of ATP and related purines in urinary tract physiology has been established over the last five decades through the work of many independent groups, inspired by, and building on the pioneering studies of Professor Geoffrey Burnstock and his coworkers. As part of a series of reviews in this tribute edition, the present article summarises our current understanding of purines and purinergic signalling in modulating and regulating urinary tract function. Purinergic mechanisms underlying the origin of bladder pain; sensations of bladder filling and urinary tract motility; and regulation of detrusor smooth muscle contraction are described, encompassing the relevant history of discovery and consolidation of knowledge as methodologies and pharmacological tools have developed. We consider normal physiology, including development and ageing and then move to pathophysiology, discussing the causal and consequential contribution of purinergic signalling mechanism and their constituent components (receptors, signal transduction, effector molecules) to bladder dysfunction.

Background: Malnutrition in hospitals remains highly prevalent. As part of quality improvement initiatives, the RCP recommends nutrition screening for all patients admitted with acute stroke. We aimed to examine the associations of patients at risk of malnutrition with outcomes following an acute stroke and their requirements of early support on discharge.Methods: We analysed prospectively collected data from four hyperacute stroke units (HASU) (2014-2016). Nutritional status was screened in 2962 acute stroke patients without prestroke disability (1,515 men, mean age±SD=73.5yr ±13.1, and 1,447 women, 79.2yr±13.0). The risk of malnutrition was tested against stroke outcomes and support on discharge, adjusted for age, sex, and comorbidities using logistic regression.Results: Risk of malnutrition was identified in 25.8% of patients; all of whom were reviewed by a dietitian by 1.3days (IQR=0.3-3.2). Compared to well-nourished patients, those at risk of malnutrition had, within 7days of admission, increased risk of poststroke adverse outcomes including: LOS on HASU>14 days, OR=9.9 (7.3-11.5); disability on discharge, OR=8.1 (6.6-10.0); worst level of consciousness in the first 7-days (score≥1), OR=7.5 (6.1-9.3); mortality, OR=5.2 (4.0-6.6); pneumonia, OR= 5.1 (3.9-6.7) and urinary tract infection, OR =1.5 (1.1-2.0). They also required greater support on discharge including: palliative care, OR =12.3 (8.5-17.8); discharge to new care home, OR=3.07 (2.18-4.3); activities of daily living support, OR=1.8 (1.5-2.3); planned joint-care, OR=1.5 (1.2-1.8) and weekly visits, OR=1.4 (1.1-1.8).Conclusions: Patients at risk of malnutrition more commonly have multiple adverse outcomes following acute stroke and greater need for early support on discharge.

There are many causes of hypercalcaemia including hyperparathyroidism, drugs, granulomatous disorders and malignancy. Parathyroid hormone (PTH) related hypercalcaemia is most commonly caused by primary hyperparathyroidism (PHPT) and more rarely by familial hypocalciuric hypercalcaemia (FHH). Algorithms for diagnosis of PTH related hypercalcaemia require assessment of a 24-h urinary calcium and creatinine excretion to calculate calcium/creatinine clearance ratio and radiological investigations including ultrasound scan and99mTc-sestamibi-SPECT/CT. To illustrate investigations and management of parathyroid-related hypercalcaemia, we present a selection of distinct cases of PHPT due to eutopic and ectopic parathyroid adenomas, as well as a case with a syndromic form of PHPT (multiple endocrine neoplasia type 1), and a case with FHH type 1 due to aCASRinactivating mutation. Additional cases with normocalcaemic hyperparathyroidism and secondary hyperparathyroidism are included for completeness of differential diagnosis. The common eutopic parathyroid adenomas are easily treated with parathyroidectomy while the less common ectopic parathyroid adenomas require more complex investigations and operative procedures such as video-assisted thoracoscopic surgery. On the other hand, the much less common FHH does not require treatment. Assessment of kin with FHH is important to identify members with this inherited condition in order to prevent unnecessary interventions.

Objectives: The National Institute of Health and Clinical Excellence and The Royal College of Physicians recommend transferring thrombolysed patients with stroke to a hyperacute stroke unit (HASU) within 4 h from hospital arrival (TArrival-HASU), but there is paucity of evidence to support this cut-off. We assessed if a shorter interval within this target threshold conferred a significant improvement in patient mortality. Design: We conducted a retrospective analysis of prospectively collected data from the Sentinel Stroke National Audit Programme. Setting: Four major UK hyperacute stroke centres between 2014 and 2016. Participants: A total of 183 men (median age = 75 years, IQR = 66–83) and 169 women (median age = 81 years, IQR = 72.5–88) admitted with acute ischaemic stroke. Main outcome measures: We evaluated TArrival-HASU in relation to inpatient mortality, adjusted for age, sex, co-morbidities, stroke severity, time between procedures, time and day on arrival. Results: There were 51 (14.5%) inpatient deaths. On ROC analysis, the AUC (area under the curve) was 61.1% (52.9–69.4%, p = 0.01) and the cut-off of TArrival-HASU where sensitivity equalled specificity was 2 h/15 min (intermediate range = 30 min to 3 h/15 min) for predicting mortality. On logistic regression, compared with the fastest TArrival-HASU group within 2 h/15 min, the slowest TArrival-HASU group beyond upper limit of intermediate range (≥ 3 h/15 min) had an increased risk of mortality: 5.6% vs. 19.6%, adjusted OR = 5.6 (95%CI:1.5–20.6, p = 0.010). Conclusions: We propose three new alarm time zones (A1, A2 and A3) to improve stroke survival: “A1 Zone” (TArrival-HASU < 2 h/15 min) indicates that a desirable target, “A2 Zone” (TArrival-HASU = 2 h/15 min to 3 h/15 min), indicates increasing risk and should not delay any further, and “A3 Zone” (TArrival-HASU ≥ 3 h/15 min) indicates high risk and should be avoided.

Background There exist wide variations in healthcare quality within the National Health Service (NHS). A shorter hospital length of stay (LOS) has been implicated as premature discharge, that may in turn lead to adverse consequences. We tested the hypothesis that a short LOS might be associated with increased risk of readmissions within 28 days of hospital discharge and also post-discharge mortality. Methods We conducted a single-centred study of 32,270 (46.1% men) consecutive alive-discharge episodes (mean age = 64.0 years, standard deviation = 20.5, range = 18-107 years), collected between 01/04/2017 and 31/03/2019. Associations of LOS tertiles (middle tertile as a reference) with readmissions and mortality were assessed using observed/expected ratios, and logistic and Cox regressions to estimate odds (OR) and hazard ratios (HR) (adjusted for age, sex, patients’ severity of underlying health status and index admissions), with 95% confidence intervals (CI). Results The observed numbers of readmissions within 28 days of hospital discharge or post-discharge mortality were lower than expected (observed: expected ratio 1) in patients in the top tertile (>4.3 days), amongst all ages. Patients in the top tertile of LOS had increased risks for one readmission: OR = 2.32 (95%CI = 1.86-2.88) or ≥2 readmissions: OR = 6.17 (95%CI = 5.11-7.45), death within 30 days: OR = 2.87 (95%CI = 2.34-3.51), and within six months of discharge: OR = 2.52 (95%CI = 2.23-2.85), and death over a 2-year period: HR = 2.25 (95%CI = 2.05-2.47). The LOS explained 7.4% and 15.9% of the total variance (r2) in one readmission and ≥2 readmissions, and 9.1% and 10.0% of the total variance in mortality with 30 days and within six months of hospital discharge, respectively. Within the bottom, middle and top tertiles of the initial LOS, the median duration from hospital discharge to death progressively shortened from 136, 126 to 80 days, whilst LOS during readmission lengthened from 0.4, 0.9 to 2.8 days, respectively. Conclusion Short LOS in hospital was associated with favourable post-discharge outcomes such as early readmission and mortality, and with a delay in time interval from discharge to death and shorter LOS in hospital during readmission. These findings indicate that timely discharge from our hospital meets the aims of the NHS-generated national improvement programme, Getting It Right First Time (GIFTR).

The LACE index scoring tool has been designed to predict hospital readmissions in adults. We aimed to evaluate the ability of the LACE index to identify children at risk of frequent readmissions. We analysed data from alive-discharge episodes (1 April 2017 to 31 March 2019) for 6546 males and 5875 females from birth to 18 years. The LACE index predicted frequent all-cause readmissions within 28 days of hospital discharge with high accuracy: the area under the curve = 86.9% (95% confidence interval = 84.3–89.5%, p 4 (event rates, 3.7%) were at increased risk of frequent readmissions: age- and sex-adjusted odds ratio = 12.4 (95% confidence interval = 8.0–19.2, p Conclusion: The LACE index can be used in healthcare services to identify children at risk of frequent readmissions. Focus should be directed at individuals with a LACE index score above 4 to help reduce risk of readmissions. What is Known:• The LACE index scoring tool has been widely used to predict hospital readmissions in adults. What is New:• Compared with children with a LACE index score of 0–4 (event rates, 0.3%), those with a score > 4 are at increased risk of frequent readmissions by 14-fold.• The cutoff of a LACE index of 4 may be a useful level to identify children at increased risk of frequent readmissions.

Paroxysmal atrial fibrillation (PAF) is the most common cardiac arrhythmia, conveying a stroke risk comparable to persistent AF. It poses a significant diagnostic challenge given its intermittency and potential brevity, and absence of symptoms in most patients. This pilot study introduces a novel biomarker for early PAF detection, based upon analysis of sinus rhythm ECG waveform complexity. Sinus rhythm ECG recordings were made from 52 patients with (n = 28) or without (n = 24) a subsequent diagnosis of PAF. Subjects used a handheld ECG monitor to record 28-second periods, twice-daily for at least 3 weeks. Two independent ECG complexity indices were calculated using a Lempel-Ziv algorithm: R-wave interval variability (beat detection, BD) and complexity of the entire ECG waveform (threshold crossing, TC). TC, but not BD, complexity scores were significantly greater in PAF patients, but TC complexity alone did not identify satisfactorily individual PAF cases. However, a composite complexity score (h-score) based on within-patient BD and TC variability scores was devised. The h-score allowed correct identification of PAF patients with 85% sensitivity and 83% specificity. This powerful but simple approach to identify PAF sufferers from analysis of brief periods of sinus-rhythm ECGs using hand-held monitors should enable easy and low-cost screening for PAF with the potential to reduce stroke occurrence.

Background Stress from obstructive sleep apnoea (OSA) stimulates catecholamine release and consequently can exacerbate hypertension, even in the absence of a catecholamine-producing tumour (phaeochromocytoma). As such, a positive screening test for suspected phaeochromocytoma may be misleading. There exists only a handful case reports, and no controlled trials, how continuous positive airway pressure (CPAP) to treat OSA influences catecholamine levels. We examined changes to levels of urinary catecholamine and blood pressure in response to CPAP treatment. Methods We conducted a meta-analysis of data aggregated from published case reports of individual patient data up to April 2020. The quality of the reports was evaluated using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool. Results A total of 13 cases (seven men and six women) from seven reports met our search criteria. Patients had mean age of 49.1 years (range = 36–62) and body mass index of 37.4 kg/m2 (range = 27–56). Most had moderate to severe OSA with CPAP treatment. Nine cases had 24-hour urinary noradrenaline assessment before and after CPAP treatment. CPAP treatment led to a 21% reduction (104 nmol/24-hours, 95% credible interval =59 to 148) in 24-hour urinary noradrenaline to within reference ranges, and 25% reduction (from 131 to 100 mmHg) in mean arterial pressure. The risk of overall bias evaluated by the ROBINS-I tool was found to be low in the majority of reports. Conclusions Investigations of patients suspected of phaeochromocytoma, particularly obese individuals, should exclude OSA and treat this condition if present before performing screening tests to assess for catecholamine levels.

Background Smoking and dyslipidaemia are known individual risk factors of coronary artery disease (CAD). The present study examined the combined risk of smoking and dyslipidaemia on coronary atherosclerosis. Methods Coronary artery calcium (CAC), measured by cardiac CT, was used to assess the extent of CAD, which was related to smoking and dyslipidaemia using logistic regression, adjusted for age, sex, hypertension, BMI and family history of ischaemic heart disease. Results Seventy-one patients (46 men, 25 women: median age of 53.7yrs; IQR = 47.0–59.5) were recruited. The mean log10 CAC score in never-smokers without dyslipidaemia (reference group) was 0.37 (SD = 0.73), while the value in those with a history of smoking was 0.44 ± 0.48 (mean difference: 0.07, 95%CI:–0.67 to 0.81, p = 0.844), dyslipidaemia was 1.07 ± 1.08 (mean difference: 0.71, 95%CI: 0.24 to 1.17, p = 0.003), and both risk factors was 1.82 ± 0.64 (mean difference: 1.45, 95%CI:0.88 to 2.02, p Conclusions Smoking and dyslipidaemia together are associated with high coronary artery calcification and CAD, independent of other major risk factors.

Background: The Royal College of Physicians recently introduced the 4AT (Alertness, Abbreviated Mental Test-4, Attention and Acute change or fluctuating course) for screening patient cognitive impairment and delirium. The 4AT and nutritional status are both indicators of health status, but their relationship has not been studied. Here, we examined the association of the 4AT with nutritional status in patients admitted to a single hospital with hip fractures between January 1, 2016 and June 6, 2019.Methods: Nutritional status was assessed using the Malnutrition Universal Screening Tool (MUST) protocol and the 4AT was assessed within 1-day after hip surgery. Differences between categorical outcome variables were tested with chi-squared tests, and logistic regression was conducted to assess the association of nutritional status (dependent variable) with 4AT scores (independent variable).Results: From 1082 patients (298 men, 784 women: mean age 83.8 ±8.7 (SD) years, range=60-103) categorized into 4AT scores of 0, 1-3 or ≥4, the prevalence of malnutrition risk was 15.5, 27.3 and 39.6% and for malnourishment were 4.1, 13.2 and 11.3%, respectively. After age and sex adjustment, compared with the 4AT=0 cohort, a 4AT score of 1-3 was associated with an increased malnutrition risk: (odds ratio (OR)=2.3, 95% confidence interval (CI)=1.6-3.1), or malnutrition itself (OR =3.6, 95%CI=2.1-6.3). For a 4AT score ≥4 corresponding ORs were 4.0 (95%CI=2.8-5.9) and 3.6 (95%CI=1.9-6.8) . These associations persisted with additional adjustments for polypharmacy, anticholinergic burden and co-morbidities including dementia, stroke and Parkinson’s disease. Overall, there was a significant positive association, whereby as 4AT scores increased, so also did malnutrition risk.Conclusions: Among older adults admitted with hip fractures, high 4AT scores, suggestive of cognitive impairment and delirium, identified patients at increased malnutrition risk. These findings lend further support for the use of 4AT as a screening tool to identify patients, who are in an acute setting, at increased health risk.

The LACE index has been shown to predict hospital readmissions and death with variable accuracy. A LACE index ≥ 10 is considered as high risk in the existing literature. We aimed to derive age-specific LACE index thresholds in the prediction of mortality and frequent readmissions. Analysis of prospectively collected data of consecutive alive-discharge episodes between 01/04/2017 and 31/03/2019 to a single hospital was conducted. The derivation of LACE index thresholds for predicting all-cause mortality within 6 months of hospital discharge or frequent readmissions (≥ 2 times within 28 days) was examined by receiver operating characteristics (ROC) in 32270 patients (14878 men, 17392 women) aged 18–107 year (mean = 64.0 years, SD = 20.5). For all patients with a LACE index ≥ 10, the area under the curve (AUC) for predicting mortality was 80.5% (95% CI 79.7–81.3) and for frequent readmissions was 84.0% (83.0–85.1). Two-graph ROC plots showed that the LACE index threshold where sensitivity equates specificity was 9.5 (95% intermediate range = 5.6–13.5) for predicting mortality and 10.3 (95% intermediate range = 6.6–13.6) for frequent readmissions. These thresholds were lowest among youngest individuals and rose progressively with age for mortality prediction: 18–49 years = 5.0, 50–59 years = 6.5, 60–69 years = 8.0, 70–79 years = 9.8 and ≥ 80 years = 11.6, and similarly for frequent readmissions: 18–49 years = 5.1, 50–59 years = 7.5, 60–69 years = 9.1, 70–79 years = 10.6 and ≥ 80 years = 12.0. Positive and negative likelihood ratios (LRs) ranged 1.5–3.3 and 0.4-0.6 for predicting mortality, and 2.5–4.4 and 0.3–0.6 for frequent readmissions, respectively, with stronger evidence in younger than in older individuals (LRs further from unity). In conclusion, the LACE index predicts mortality and frequent readmissions at lower thresholds and stronger in younger than in older individuals. Age should be taken into account when using the LACE index for identifying patients at high risk. Electronic supplementary material The online version of this article (10.1007/s11739-020-02448-3) contains supplementary material, which is available to authorized users.

Aim: To discuss animal models of lower urinary tract disorders (LUTD) and their translational impact. Methods: Report of discussions based on presented literature-search based reviews relevant for the purpose. Results: Animal models can be used to investigate fundamental biological mechanisms, but also as tools to elucidate aspects of the pathogenesis of disease and to provide early evidence of any safety risk. Several different models may be required to obtain information that can have a translational impact. The term “translational research” covers not only the process of directly transferring knowledge from basic sciences to human trials to produce new drugs, devices, and treatment options for patients (T1 type translation) but also the implementation of early clinical research findings (phases I-III) into practice to improve care for patients (T2 type). Direct transfer of animal data to T2 is rarely possible, and the process often does not continue after the first trials in humans (phase I). It should be emphasized that many preclinical observations do not have (and do not need to have) immediate translational impact. Conclusions: No single animal model can mimic the complexity of the human disease. Still, animal models can be useful for gaining information on LUT function in humans, for elucidating pathophysiological mechanisms, and for the definition of targets for future drugs to treat LUT disorders. (Less)

AIMS: Bladder wall stretch increases tissue tension and releases adenosine 5'-triphosphate (ATP) as part of a transduction process to sense bladder filling. Aging is associated with bladder fibrosis to produce a stiffer bladder wall: this may augment ATP release and contribute to age-dependent urgency. Muscarinic agonists also release ATP and present a potential target for antimuscarinic agents, but its age-dependency is unknown. This study aimed, in young and old mice, to: (a) quantify the relationship between bladder wall stiffness and stretch-dependent ATP release and; (b) characterize muscarinic agonist-dependent release.METHODS: ATP release from young (9-12 weeks) and aged (24 months) mouse bladder wall was measured in vitro, with a luciferin-luciferase assay, after stretch or carbachol exposure. Bladder wall stiffness, measured simultaneously during stretch, was compared to histological proportions of connective tissue and detrusor muscle.RESULTS: With young mice, stretch-activated ATP release required an intact mucosa and was positively associated with wall stiffness. ATP release by carbachol was about four-fold greater compared to stretch. With aged mice: ATP release varied a hundred-fold and no association with stiffness; carbachol release diminished; connective tissue and mucosa thickness increased.CONCLUSIONS: With young mice, stretch, or muscarinic agonists potently induce bladder wall ATP release. Stretch-dependent release is proportional to bladder wall stiffness, independent of the extent of stretch. With aged mice dependence of stretch-activated ATP release with stiffness was lost. The huge variability of release suggests that aged mice do not form a homogenous cohort and may underlie the heterogeneity in bladder filling sensations.

BACKGROUND/OBJECTIVES: Major causes of hip fractures are osteoporosis and falls, both of which are determined by nutrition. Information on the nutritional status of patients admitted to hospital with a hip fracture is lacking. In this study, we assessed determinants and adverse outcomes associated with malnutrition and malnourishment. METHODS: Nutritional status, assessed using the Malnutrition Universal Screening Tool protocol, was compared to age and residency prior to admission, and outcomes during hospital stay and at discharge. RESULTS: A total of 1239 patients admitted with a hip fracture (349 men, 890 33 women), aged 60-100yr. Compared with well-nourished individuals, the prevalences of malnutrition risk or malnourishment were higher in older age groups and those from residential or nursing care. Those with risk of malnutrition or malnourishment stayed in hospital longer by 3.0 days (95% confidence interval (CI), 1.5-4.5 days; 37 pCONCLUSIONS: Inadequate nutrition is common in patients admitted to hospital with a hip fracture, which in turn predisposes them to a number of complications. More research on nutritional support should be directed to this group to prevent or minimise hip fractures.

Summary Introduction Posterior urethral valves (PUV) is the most common cause of congenital bladder outflow obstruction with persistent lower urinary tract and renal morbidities. There is a spectrum of functional bladder disorders ranging from hypertonia to bladder underactivity, but the aetiology of these clinical conditions remains unclear. Aims and objectives We tested the hypothesis that replacement of detrusor muscle with non-muscle cells and excessive deposition of connective tissue is an important factor in bladder dysfunction with PUV. We used isolated detrusor samples from children with PUV and undergoing primary or secondary procedures in comparison to age-matched data from children with functionally normal bladders. In vitro contractile properties, as well as passive stiffness, were measured and matched to histological assessment of muscle and connective tissue. We examined if a major pathway for fibrosis was altered in PUV tissue samples. Methods Isometric contractions were measured in vitro in response to either stimulation of motor nerves to detrusor or exposure to cholinergic and purinergic receptor agonists. Passive mechanical stiffness was measured by rapid stretching of the tissue and recording changes to muscle tension. Histology measured the relative amounts of detrusor muscle and connective tissue. Multiplex quantitative immunofluorescence labelling using five epitope markers was designed to determine cellular pathways, in particular the Wnt-signalling pathway, responsible for any changes to excessive deposition of connective tissue. Results and Discussion PUV tissue showed equally reduced contractile function to efferent nerve stimulation or exposure to contractile agonists. Passive muscle stiffness was increased in PUV tissue samples. The smooth muscle:connective tissue ratio was also diminished and mirrored the reduction of contractile function and the increase of passive stiffness. Immunofluorescence labelling showed in PUV samples increased expression of the matrix metalloproteinase, MMP-7; as well as cyclin-D1 expression suggesting cellular remodelling. However, elements of a fibrosis pathway associated with Wnt-signalling were either reduced (β-catenin) or unchanged (c-Myc). The accumulation of extracellular matrix, containing collagen, will contribute to the reduced contractile performance of the bladder wall. It will also increase tissue stiffness that in vivo would lead to reduced filling compliance. Conclusions Replacement of smooth muscle with fibrosis is a major contributory factor in contractile dysfunction in the hypertonic PUV bladder. This suggests that a potential strategy to restore normal contractile and filling properties is development of the effective use of antifibrotic agents. Download : Download high-res image (132KB) Download : Download full-size image Summary Figure .

Micturition requires precise control of bladder and urethral sphincter via parasympathetic, sympathetic and somatic motoneurons. This involves a spino-bulbospinal control circuit incorporating Barrington’s nucleus in the pons (Barr). Ponto-spinal glutamatergic neurons that express corticotrophin-releasing hormone (CRH) form one of the largest Barr cell populations. BarrCRH neurons can generate bladder contractions, but it is unknown whether they act as a simple switch or provide a high-fidelity pre-parasympathetic motor drive and whether their activation can actually trigger voids. Combined opto- and chemo-genetic manipulations along with multisite extracellular recordings in urethane anaesthetised CRHCre mice show that BarrCRH neurons provide a probabilistic drive that generates co-ordinated voids or non-voiding contractions depending on the phase of the micturition cycle. CRH itself provides negative feedback regulation of this process. These findings inform a new inferential model of autonomous micturition and emphasise the importance of the state of the spinal gating circuit in the generation of voiding.